Selenium deficiency has been associated with an increased risk of prostate, esophageal, gastric, lung, thyroid and ovarian cancer, colonic adenomas, and hepatocellular carcinoma. Selenium deficiency has also been correlated with accelerated disease progression and increased mortality in both HIV-infected children and adults. In animal models selenium deficiency is associated with enhanced oxidative stress, anthracycline induced cardiotoxicity and virulent Coxsackie virus infection. In humans selenium supplementation may reduce the rate of specific cancers including lung, prostate, and colon. In the form of selenocysteine (the 21st amino acid), selenium is incorporated into the primary structure of at least 16 human proteins, most of which have important antioxidant properties. Given the important role that selenium and selenoenzymes play in protecting against oxidative stress, it is possible that genetic variations in selenoenzymes may be risk factors for specific cancers or for severe inflammatory or infectious complications of disease. To help unravel the role of selenium in cancer and infectious diseases, this grant proposes to identify and confirm novel SNPs in selenium containing genes, with a focus on glutathione peroxidase and thioredoxin reductase. Functional studies will define the biologic importance of SNPs and haplotypes. The generated data will provide a critical foundation for interpreting clinical association studies designed to correlate genetic variants in selenoenzyme genes with risk of HIV progression or of developing cancer.